Abstract
IntroductionFocal and Segmental GlomeruloSclerosis (FSGS) can cause nephrotic syndrome with a risk of progression to end-stage renal disease. The idiopathic form has a high rate of recurrence after transplantation, suggesting the presence of a systemic circulating factor that causes glomerular permeability and can be removed by plasmapheresis or protein-A immunoadsorption.ResultsTo identify this circulating factor, the eluate proteins bound on therapeutic immunoadsorption with protein-A columns were analyzed by comparative electrophoresis and mass spectrometry. A soluble form of calcium/calmodulin-dependent serine protein kinase (CASK) was identified. CASK was immunoprecipitated only in the sera of patients with recurrent FSGS after transplantation and not in control patients. Recombinant-CASK (rCASK) induced the reorganization of the actin cytoskeleton in immortalized podocytes, a redistribution of synaptopodin, ZO-1,vinculin and ENA. rCASK also induced alterations in the permeability of a monolayer of podocytes and increased the motility of pdodocytes in vitro. The extracellular domain of CD98, a transmembrane receptor expressed on renal epithelial cells, has been found to co-immunoprecipitated with rCASK. The invalidation of CD98 with siRNA avoided the structural changes of rCask treated cells suggesting its involvement in physiopathology of the disease. In mice, recombinant CASK induced proteinuria and foot process effacement in podocytes.ConclusionOur results suggest that CASK can induce the recurrence of FSGS after renal transplantation.
Highlights
Our results suggest that calmodulin-dependent serine protein kinase (CASK) can induce the recurrence of Focal and Segmental GlomeruloSclerosis (FSGS) after renal transplantation
Three patients with rFSGS after renal transplantation were treated by serum immunoadsorption using protein-A columns as soon as the diagnosis of recurrence was made
Five different peptides, which complied with the acceptance threshold, were identified and corresponded to CASK a calcium/calmodulin-dependent-serine protein kinase which participates to the cytoskeleton scaffold in many cells and have been demonstrated to bind to the extracellular domain of CD98
Summary
Three patients with rFSGS after renal transplantation were treated by serum immunoadsorption using protein-A columns as soon as the diagnosis of recurrence was made. Eight patients with rFSGSoccuring rapidly, during the first three weeks after renal transplantation have been studied They were treated by immunoadsorptions or plasma exchanges resulting in a consistent strong reduction of proteinuria for all of them (median proteinuria reduction 85%) (Table 1). Previous studies have demonstrated that an extracellular form of CASK is capable of binding CD98 on Caco-2 cells [20,21]) To investigate such an interaction in podocytes, we incubated these cells with either a c-myc-tagged rCASK (Fig 5Aa) or plasma from rFSGS patients (Fig 5Ab).
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